Recent studies suggest that a class of substituted amphetamines, which includes p-chloroamphetamine, causes an acute release of serotonin (5-hydroxytryptamine) and appears to act preferentially on axons arising from the dorsal raphe nucleus. The postsynaptic targets of these axons are not well characterized, but they have been localized in close proximity to the distribution of serotonin2A receptor binding sites. In the present study, c-fos immunocytochemistry has been used to investigate this anatomical relationship further. Administration of p-chloroamphetamine or the serotonin2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane to rats resulted in similar patterns of Fos-like immunoreactivity in some, but not all, forebrain areas. Areas which expressed Fos following either treatment included cerebral cortex, claustrum, amygdala and nucleus accumbens. A particularly close match was seen in layer Va of the somatosensory cortex. No specificity of p-chloroamphetamine for dorsal raphe nucleus-innervated areas was noted. Prior treatment of animals with p-chloroamphetamine two weeks before a second challenge with the same drug, or with the serotonin2A/2C receptor antagonist ritanserin 30 min before p-chloroamphetamine challenge, resulted in an attenuation of p-chloroamphetamine-induced Fos-like immunoreactivity in the olfactory tubercle, the islands of Calleja and the caudate-putamen. The reduction was most noticeable in layer Va of the somatosensory cortex. The results of this study indicate that a close anatomical correlation may exist between the fine serotonin axon terminals that show vulnerability to the neurotoxic effects of p-chloroamphetamine and serotonin2A receptors in some brain regions. This association may prove to be important in explaining the actions of certain psychotropic drugs, for example in the control of affective states.